Amphotericin B (AmB) is a polyene antifungal agent, first isolated by Gold, et al. from Streptomyces nodosus in 1955. It is an amphoteric compound composed of a hydrophilic polyhydroxyl chain along one side and a lipophilic polyene hydrocarbon chain on the other. Amphotericin B is poorly soluble in water (Terrell, C. L. and C. E. Hughes, Mayo Clin Proc, 1992. 67(1): 69-91). Commonly, the use of AmB has been limited by its toxicity profile, and especially by hypersensitivity reactions and nephrotoxicity (Gafter-Gvili, A., et al., Mayo Clin Proc, 2008. 83(9): 1011-21). Infusion related hypersensitivity is one of the most common adverse events associated with AmB treatment. A series of acute reactions such as high fever, chills, hypotension and tachycardia are often noted shortly (1 to 3 hours) after the amphotericin infusion. Premedication with diphenhydramine and acetaminophen are often indicated for preventing and alleviating these symptoms. Nephrotoxicity is another major side effect. AmB induced nephrotoxicity is dose limiting, and it can be severe and irreversible. Clinical manifestations include azotemia, decreased glomerular filtration, loss of urinary concentrating ability, loss of renal electrolytes, and renal tubular acidosis (Meyer, R. D. Clin Infect Dis, 1992. 14: S154-60). In addition, AmB is known to cause anemia, which is thought to be due to a reduction of erythropoietin production (Lin, A. C., et al. J Infect Dis, 1990. 161(2): 348-51). Currently, amphotericin B is available in four formulations: amphotericin B deoxycholate (Fungizone®), amphotericin lipid complex (ABLC), amphotericin B colloidal dispersion (ABCD), and liposomal amphotericin (AmBisome® or L-AMB). In general, the lipid formulations of AmB demonstrate better tolerability, and they display significantly different plasma pharmacokinetics (Vogelsinger, H., et al. J Antimicrob Chemother, 2006. 57(6): 1153-60).
Recently, a novel lipid formulation of AmB was reported. AmB was incorporated into water-soluble, nanometer-scale reconstituted high-density lipoprotein-like particles, termed nanodiscs (ND). AmB-ND particles have a phospholipid bilayer, with edges stabilized by apolipoprotein to form a disk-shaped structure. The AmB-ND formulation exhibited potent in vitro and in vivo antifungal activity. However, the protein-containing nanodiscs suffer from drawbacks including increased production cost and risk of bacterial toxin contamination associated with the use of recombinant apolipoprotein (Oda, M. N., et al. J Lipid Res, 2006. 47(2): 260-7; Tufteland, M., et al. Peptides, 2007. 28(4): 741-6), the propensity for apolipoprotein to target hepatocytes, as well as a tendency for such AmB-ND to aggregate which limits clinical applications. Therefore, a need exists for improved formulations for drug delivery in general, as well as for more stable and convenient lipid-based formulations in particular. Surprisingly, the invention as described herein addresses these and other needs.